US6841566B2ExpiredUtilityPatentIndex 91
Viral polymerase inhibitors
Est. expiryJul 20, 2021(expired)· nominal 20-yr term from priority
Inventors:BEAULIEU PIERRE LOUISFAZAL GULREZGOULET SYLVIEKUKOLJ GEORGEPOIRIER MARTINTSANTRIZOS YOULA S
C07D 405/04C07D 471/04C07D 235/18C07D 409/14C07D 403/04C07D 409/04C07D 401/04A61P 31/12C07D 405/14C07D 417/14A61P 43/00A61P 31/22
91
PatentIndex Score
35
Cited by
10
References
62
Claims
Abstract
An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: wherein R 1 is selected from: H, haloalkyl, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 3-7 )cycloalkyl, (C 2-6 )alkynyl, (C 5-7 )cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R 2 is selected from (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 6-10 )bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR 5 , wherein R 5 is H, halogen, haloalkyl, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; X is N or CR 5 ; D is N or CR 5 ; each of Y 1 and Y 2 is independently O or S; Z is O, N, or NR Z wherein R Z is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl or 6- or 10-membered aryl, Het (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het; or each R 3 and R 4 are independently covalently bonded together to form second (C 3-7 )cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R 3 or R 4 are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R 7 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; or R 7 is covalently bonded to either of R 3 or R 4 to form a heterocycle; A is (C 1-6 )alkyl-CONHR 8 wherein R 8 is -6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.
Claims
exact text as granted — not AI-modified1. An isomer, enantiomer, diastereoisomer, or tautomer of a compound represented by formula I:
wherein
R 1 is selected from: R 11 , OR 11 , SR 11 , COOR 11 , SO 2 N(R 12 ) 2 , N(R 12 ) 2 , CON(R 12 ) 2 ,
NR 12 C(O)R 12 or NR 12 C(O)NR 12 wherein R 11 and each R 12 is independently H, (C 1-6 alkyl, haloalkyl, (C 2-6 )alkenyl, (C 3-7 )cycloalkyl, (C 2-6 )alkynyl, (C 5-7 )cycloalkenyl, 6 or 10-membered aryl or Het, said R 11 and R 12 being optionally substituted with R 10 ; or both R 12 are bonded together to form a 5, 6 or 7-membered saturated heterocycle with the nitrogen to which they are attached;
R 2 is selected from (C 1-6 )alkyl, haloalkyl, (C 3-7 )cycloalkyl, (C 5-7 )cycloalkenyl, (C 6-10 )bicycloalkyl, (C 6-10 )bicycloalkenyl, 6- or 10-membered aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het,
said alkyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, aryl, Het, alkyl-aryl and alkyl-Het being optionally substituted with from 1 to 4 substituents selected from: halogen, or
a) (C 1-6 )alkyl optionally substituted with:
OR 21 or SR 21 wherein R 21 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het; or
N(R 22 ) 2 wherein each R 22 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het; or both R 22 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
b) OR 23 wherein R 23 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het;
c) SR 24 wherein R 24 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het; and
d) N(R 25 ) 2 wherein each R 25 is independently H, (C 1-6 alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het; or both R 25 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
B is CR 6 , wherein R 5 is H, halogen, (C 1-6 )alkyl, haloalkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; or R 5 is OR 51 or SR 51 , COR 51 or NR 51 COR 51 wherein each R 51 is independently H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
or R 5 is NR 52 R 53 wherein R 52 and R 53 are each independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, or both R 52 and R 53 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
X is CR 5 , wherein R 5 is as defined above;
D is CR 5 , wherein R 5 is as defined above;
each of Y 1 and Y 2 is independently O or S;
Z is O, N, or NR 6 wherein R 6 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
R 3 and R 4 are each independently H, (C 1-6 )alkyl, haloalkyl, (C 3-7 )cycloalkyl, 6- or 10-membered aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 alkyl-Het, wherein said alkyl, cycloalkyl, aryl; Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het are optionally substituted with R 30 ; or
R 7 and R 8 are covalently bonded together to form second (C 3-7 )cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; or when Z is NR 6 , either of R 7 or R 8 is covalently bonded to R 6 to form a nitrogen-containing 5- or 6-membered heterocycle;
R 7 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het, all of which optionally substituted with R 70 ; or
R 7 is covalently bonded to either of R 3 or R 4 to form a 5- or 6-membered heterocycle;
A is a 6- or 10-membered aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het, (C 1-6 )alkyl-CONH-aryl or (C 1-6 )alkyl-CONH-Het, all of which being optionally substituted with:
or a salt or a derivative thereof;
wherein Het is defined as:
5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9- or 10-membered heterobicycle having 1 to 5 heteroatoms selected from O, N and S; and
R 10 , R 30 , R 70 and R 100 are defined as:
1 to 4 substituents selected from: halogen, OPO 3 H, NO 2 , cyano, azido, C(═NH)NH 2 , C(═NH)NH(C 1-6 )alkyl or C(═NH)NHCO(C 1-6 )alkyl; or
1 to 4 substituents selected from:
a) (C 1-6 )alkyl or haloalkyl, (C 3-7 )cycloalkyl, C 3-7 spirocycloalkyl optionally containing 1 or 2 heteroatom, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, all of which optionally substituted with R 150 ;
b) OR 104 wherein R 104 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 150 ;
c) OCOR 105 wherein R 105 is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 cycloalkyl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 150 ;
d) SR 105 , SO 2 N(R 105 ) 2 or SO 2 N(R 105 )C(O)R 105 wherein each R 105 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or both R 105 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or heterocycle being optionally substituted with R 150 ;
e) NR 111 R 112 wherein R 111 is H, (C 1-6 alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, and R 112 is H, CN, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl, (C 1-6 alkyl)Het, COOR 115 or SO 2 R 115 wherein R 115 is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or both R 111 and R 112 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or heterocycle being optionally substituted with R 150 ;
f) NR 116 COR 117 wherein R 116 and R 117 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 150 ;
g) NR 118 CONR 119 R 120 , wherein R 118 , R 119 and R 120 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or R 118 is covalently bonded to R 119 and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
or R 119 and R 120 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or heterocycle being optionally substituted with R 150 ;
h) NR 121 COCOR 122 wherein R 121 and R 122 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, a 6- or 10-membered aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 150 ;
or R 122 is OR 123 or N(R 124 ) 2 wherein R 123 and each R 124 is independently H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or R 124 is OH or O(C 1-6 alkyl) or both R 124 are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het and heterocycle being optionally substituted with R 150 ;
i) COR 127 wherein R 127 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or(C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 150 ;
j) COOR 128 wherein R 128 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or(C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or(C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl and (C 1-6 alkyl)Het being optionally substituted with R 150 ;
k) CONR 129 R 130 wherein R 129 and R 130 are independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or both R 129 and R 130 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl, (C 1-6 alkyl)Het and heterocycle being optionally substituted with R 150 ;
l) aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, all of which being optionally substituted with R 150 ; and
wherein R 160 is defined as:
1 to 3 substituents selected from: halogen, OPO 3 H, NO 2 , cyano, azido, C(═NH)NH 2 , C(═NH)NH(C 1-6 )alkyl or C(═NH)NHCO(C 1-6 )alkyl; or 1 to 3 substituents selected from:
a) (C 1-6 )alkyl or haloalkyl, (C 3-7 )cycloalkyl, C 3-7 spirocycloalkyl optionally containing 1 or 2 heteroatom, (C 2-6 )alkenyl, (C 2-8 alkynyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, all of which optionally substituted with R 160 ;
b) OR 104 wherein R 104 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 160 ;
c) OCOR 105 wherein R 105 is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 160 ;
d) SR 108 , SO 2 N(R 108 ) 2 or SO 2 N(R 108 )C(O)R 108 wherein each R 108 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or both R 108 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or heterocycle being optionally substituted with R 160 ;
e) NR 111 R 112 wherein R 111 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, and R 112 is H, CN, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl, (C 1-6 alkyl)Het, COOR 115 or SO 2 R 115 wherein R 115 is (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or both R 111 and R 112 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or heterocycle being optionally substituted with R 160 ;
f) NR 116 COR 117 wherein R 116 and R 117 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 160 ;
g) NR 118 CONR 119 R 120 , wherein R 118 , R 119 and R 120 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or R 118 is covalently bonded to R 119 and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R 119 and R 120 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C 1-6 alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het or heterocycle being optionally substituted with R 160 ;
h) NR 121 COCOR 122 wherein R 121 and R 122 is each H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, a 6- or 10-membered aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 160 , or R 122 is OR 123 or N(R 124 ) 2 wherein R 123 and each R 124 is independently H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or R 124 is OH or O(C 1-6 alkyl) or both R 124 are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het and heterocycle being optionally substituted with R 160 ;
i) COR 127 wherein R 127 is H, (C 1-6 )alkyl, (C 3-7 cycloalkyl or (C 1-6 alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het being optionally substituted with R 160 ;
j) tetrazole, COOR 128 wherein R 128 is H, (C 1-6 )alkyl, (C 3-7 cycloalkyl, or(C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, said (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; aryl, Het, (C 1-6 alkyl)aryl and (C 1-6 alkyl)Het being optionally substituted with R 160 ; and
k) CONR 129 R 130 wherein R 129 and R 130 are independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl or (C 1-6 alkyl)Het, or both R 129 and R 130 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C 1-6 alkyl)aryl, (C 1-6 alkyl)Het and heterocycle being optionally substituted with R 160 ;
wherein R 106 is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C 1-6 alkyl, haloalkyl, COOR 161 , SO 3 H, SR 161 , SO 2 R 161 , OR 161 , N(R 162 ) 2 , SO 2 N(R 162 ) 2 , NR 162 COR 162 or CON(R 162 ) 2 , wherein R 161 and each R 162 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; or both R 162 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
and with the proviso that when R 1 is Het, R 2 is (C 3-7 )cycloalkyl, Y 1 and Y 2 are both O, Z is NH, one of R 3 and R 4 is optionally substituted (C 1-6 )alkyl-aryl or optionally substituted (C 1-6 )alkyl-Het, and R 7 is H, then A is not optionally substituted Het or optionally substituted (C 1-6 )alkyl-Het.
2. A compound according to claim 1 , wherein R 1 is selected from: (C 3-7 )cycloalkyl, (C 5-7 )cycloalkenyl, 6 or 10-membered aryl, or Het each of which being optionally substituted with 1 or 2 halogen or from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl, each optionally substituted with OR 11 , SR 11 , wherein R 11 is independently H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
b) OR 13 wherein R 13 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, a 6- or 10-membered aryl, or Het; and
f) a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted with (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl.
3. A compound according to claim 2 , wherein R 1 is selected from: 6 or 10-membered aryl, or Het each of which being optionally substituted with 1 or 2 halogen or with 1 or 2 (C 1-6 )alkyl.
4. A compound according to claim 3 , wherein R 1 is phenyl or Het optionally substituted with (C 1-6 )alkyl.
5. A compound according to claim 4 , wherein R 1 is selected from:
6. A compound according to claim 5 , wherein R 1 is selected from:
7. A compound according to claim 1 , wherein R 2 is selected from (C 3-7 )cycloalkyl, (C 6-10 )bicycloalkyl, each optionally substituted with 1 or 2 substituents selected from:
a) halogen, (C 1-6 )alkyl, OH, or (C 1-6 )alkoxy.
8. A compound according to claim 7 , wherein R 2 is selected from (C 3-7 )cycloalkyl, (C 6-10 )bicycloalkyl, each optionally mono- or di-substituted with halogen or (C 1-6 )alkyl.
9. A compound according to claim 8 , wherein R 2 is selected from (C 3-7 )cycloalkyl or (C 6-10 )bicycloalkyl.
10. A compound according to claim 9 , wherein R 2 is cyclopentyl, cyclohexyl, or
11. A compound according to claim 10 , wherein R 2 is cyclopentyl or cyclohexyl.
12. A compound according to claim 1 , wherein B is CR 5 , wherein R 5 is H, halogen, haloalkyl, or (C 1-6 )alkyl.
13. A compound according to claim 12 , wherein B is CH or C—(C 1-6 alkyl).
14. A compound according to claim 13 , wherein B is CH or C(Me).
15. A compound according to claim 14 , wherein B is CH.
16. A compound according to claim 1 , wherein X is CH or C—(C 1-6 alkyl).
17. A compound according to claim 16 , wherein X is CH or C(Me).
18. A compound according to claim 17 , wherein X is CH.
19. A compound according to claim 1 , wherein D is CR 5 , wherein R 5 is H, halogen, haloalkyl, or (C 1-6 )alkyl.
20. A compound according to claim 19 , wherein D is CH or C(Me).
21. A compound according to claim 20 , wherein D is CH.
22. A compound according to claim 1 wherein Y 1 is O.
23. A compound according to claim 1 wherein Y 2 is O.
24. A compound according to claim 1 wherein both Y 1 and Y 2 are O.
25. A compound according to claim 1 , wherein Z is N, or NH or O.
26. A compound according to claim 25 , wherein Z is NH or O.
27. A compound according to claim 26 , wherein Z is NH.
28. A compound according to claim 1 , wherein R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl, 6- or 10-membered aryl, Het (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het;
or R 3 and R 4 are independently covalently bonded together to form second (C 3-7 )cycloalkyl, 5- or 6-membered heterocycle having from 1 to 4 heteroatom selected from O, N, and S;
wherein said alkyl, first and second cycloalkyl, aryl, Het,
(C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het or heterocycle are optionally substituted with from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 2-4 )alkenyl; and
c) OR 31 or COOR 31 , wherein each R 31 is independently H or (C 1-6 )alkyl;
or when Z is N, either R 3 or R 4 are independently covalently bonded thereto to form a nitrogen-containing 5- or 6-membered heterocycle.
29. A compound according to claim 28 , wherein R 3 and R 4 are each independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl or (C 1-6 )alkyl-Het; or R 3 and R 4 are covalently bonded together to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 5- or 6-membered heterocycle having from 1 or 2 heteroatom selected from N or S;
wherein said alkyl, cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or heterocycle are optionally substituted with from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 2-4 )alkenyl; and
c) OH or COO(C 1-6 )alkyl.
30. A compound according to claim 29 , wherein R 3 and R 4 are each independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, aryl, Het, (C 1-6 )alkyl-phenyl, (C 1-6 )alkyl-Het;
or R 3 and R 4 are covalently bonded together to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl all optionally substituted with OH, (C 1-6 alkyl) or (C 2-4 )alkenyl; or R 3 and R 4 form a piperidine or a pyrrolidine both optionally substituted with (C 1-6 alkyl) or COO(C 1-6 )alkyl.
31. A compound according to claim 30 , wherein R 3 is H or (C 1-6 )alkyl and R 4 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl-aryl, aryl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, or (C 1-6 )alkyl-biaryl.
32. A compound according to claim 31 , wherein both R 3 and R 4 are H or both CH 3 ;
or R 3 is H and R 4 is selected from:
R 3 and R 4 are bonded together and form:
33. A compound according to claim 1 , wherein R 7 is H or (C 1-6 alkyl).
34. A compound according to claim 33 , wherein R 7 is H or Me.
35. A compound according to claim 34 , wherein R 7 is H.
36. A compound according to claim 1 , wherein A is a 6- or 10-membered aryl, Het or (C 1-6 )alkyl-CONH-aryl, said aryl or Het being optionally substituted with:
halogen, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, (C 1-6 ) haloalkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, all of which are optionally substituted with:
(C 1-6 )alkyl, (C 3-7 )cycloalkyl; both optionally substituted with a 6 or 10-membered aryl, or Het;
OR 101 , COOR 101 or CON(R 101 ) 2 , wherein each R 101 is independently H or (C 1-6 )alkyl;
b) OR 104 wherein R 104 is H or (C 1-6 alkyl) optionally substituted with: COOR 105 or CON(R 105 ) 2 wherein each R 105 is independently H or (C 1-6 )alkyl;
d) SR 108 wherein R 108 is H or (C 1-6 )alkyl optionally substituted with COOR 109 or CON(R 109 ) 2 , wherein each R 109 is independently H or (C 1-6 alkyl;
e) NR 111 R 112 wherein R 111 and R 112 are both H; or R 111 is H and R 112 is Het optionally substituted with (C 1-6 )alkyl or COOR 115 or CON(R 115 ) 2 , wherein each R 115 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
j) tetrazole, COOH or COO(C 1-6 )alkyl; and
k) CONR 129 R 130 wherein R 129 and R 130 are each independently H or (C 1-6 )alkyl optionally substituted with COOH or COO(C 1-6 )alkyl; and
l) 6- or 10-membered aryl or Het, said aryl or Het being optionally substituted with from 1 to 4 substituents selected from:
i) (C 1-6 )alkyl or haloalkyl;
ii) OR 104 , wherein R 104 is H, or (C 1-6 )alkyl) optionally substituted with COOH or COO(C 1-6 )alkyl; and
iii) COOR 128 , NR 111 R 112 or CON(R 129 R 130 ) 2 , wherein R 128 , R 111 , R 112 , R 129 and R 130 are independently H or (C 1-6 )alkyl.
37. A compound according to claim 36 , wherein A is a 6- or 10-membered aryl, or Het, said aryl or Het being optionally substituted with:
halogen, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-8 )alkynyl, said alkyl and alkenyl being optionally substituted with:
OH, (C 1-6 )alkoxy, COOH or CONH 2 ;
b) OH, O(C 1-6 )alkyl)COOH or O(C 1-6 alkyl)CONH 2 ;
d) SH, S(C 1-6 )alkylCOOH or S(C 1-6 )alkylCONH 2 ;
j) tetrazole, COOH or CONH 2 ; and
l) furan or thiazole mono or di-substituted with:
i) (C 1-6 )alkyl; or
iii) COOH or CONH 2 .
38. A compound according to claim 37 , wherein A is phenyl, indole, benzofuran, benzothiophene, coumarin or quinolone, all of which optionally substituted with:
iodine, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-8 )alkynyl, said alkyl and alkenyl being optionally substituted with:
OH, (C 1-6 )alkoxy, COOH or CONH 2 ;
b) OH, O(C 1-6 )alkyl)COOH or O(C 1-6 )alkyl)CONH 2 ;
d) SH, S(C 1-6 )alkylCOOH or S(C 1-6 )alkylCONH 2 ;
j) COOH or CONH 2 ; and
l) furan or thiazole mono or di-substituted with:
i) (C 1-6 )alkyl; or
iii) COOH or CONH 2 .
39. A compound according to claim 38 , wherein A is selected from:
40. A compound according to claim 39 , wherein A is selected from:
41. A compound according to claim 1 , having the following formula:
wherein R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl, 6- or 10-membered aryl, Het, (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het;
or R 3 and R 4 are independently covalently bonded together to form second (C 3-7 )cycloalkyl, 5- or 6-membered heterocycle having from 1 to 4 heteroatom selected from O, N, and S;
wherein said alkyl, first and second cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het or heterocycle are optionally substituted with from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 2-4 )alkenyl; and
c) OR 101 or COOR 101 , wherein each R 101 is independently H or (C 1-6 )alkyl; and
A is a 6- or 10-membered aryl, Het or (C 1-6 )alkyl-CONH-aryl, said aryl or Het being optionally substituted with:
halogen, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, haloalkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl, (C 2-8 )alkynyl, all of which are optionally substituted with:
second (C 1-6 )alkyl, second (C 3-7 )cycloalkyl; said second alkyl or second cycloalkyl being optionally substituted with a 6 or 10-membered aryl, or Het;
OR 101 , COOR 101 or CON(R 101 ) 2 , wherein each R 101 is independently H or (C 1-6 )alkyl;
b) OR 104 wherein R 104 is H or (C 1-6 alkyl) optionally substituted with: COOH, COO(C 1-6 )alkyl or CONH 2 ;
d) SR 108 wherein R 108 is H or (C 1-6 )alkyl optionally substituted with COOH, COO(C 1-6 )alkyl or CONH 2 ;
e) NR 111 R 112 wherein both R 111 and R 112 are H; or R 111 is H and R 112 is Het optionally substituted with (C 1-6 )alkyl, COOR 115 or CON(R 115 ) 2 , wherein each R 115 is independently H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
j) COOH or COO(C 1-6 )alkyl; and
k) CONR 129 R 130 wherein R 129 and R 130 are independently H or (C 1-6 )alkyl optionally substituted with COOH or COO(C 1-6 )alkyl; and
l) 6- or 10-membered aryl or Het, said aryl or Het being optionally substituted with from 1 to 4 substituents selected from:
i) (C 1-6 )alkyl or haloalkyl;
ii) OR 104 . wherein R 104 is H, or (C 1-6 )alkyl) optionally substituted with COOH or COO(C 1-6 )alkyl; and
iii) COOR 128 , NR 111 R 112 or CON(R 129 R 130 ) 2 , wherein R 128 , R 111 , R 112 , R 129 and R 130 are independently H or (C 1-6 )alkyl;
with the proviso that when one of R 3 and R 4 is optionally substituted (C 1-6 )alkyl-6- or 10-membered aryl or optionally substituted (C 1-6 )alkyl-Het, then A is not optionally substituted Het.
42. A compound according to claim 1 , having the following formula:
wherein
R 1 is selected from: (C 3-7 )cycloalkyl, (C 5-7 )cycloalkenyl, 6 or 10-membered aryl or Het, each of which being optionally substituted with 1 or 2 halogen or from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 3-7 )cycloalkyl, each optionally substituted with OR 11 , SR 11 , wherein R 11 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
b) OR 13 wherein R 13 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl, (C 1-6 )alkyl-(C 3-7 )cycloalkyl, a 6- or 10-membered aryl, or Het; and
f) a 6- or 10-membered aryl or Het, said aryl or Het being optionally substituted with (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
R 2 is selected from (C 3-7 )cycloalkyl, (C 6-10 )bicycloalkyl, each optionally substituted with 1 or 2 substituents selected from: halogen, (C 1-6 )alkyl, OH, and (C 1-6 )alkoxy;
R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl, 6- or 10-membered aryl, Het (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het;
or R 3 and R 4 are covalently bonded together to form second (C 3-7 )cycloalkyl, 5- or 6-membered heterocycle having from 1 to 4 heteroatom selected from O, N, and S;
wherein said alkyl, first and second cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het or heterocycle are optionally substituted with from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 2-4 )alkenyl; and
c) OR 31 or COOR 31 , wherein R 31 is H or (C 1-6 )alkyl; and
A′ is a 6- or 10-membered aryl, Het or (C 1-6 )alkyl-CONH-aryl, said aryl or Het being optionally substituted with:
halogen, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, (C 1-6 ) haloalkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl, (C 2-8 )alkynyl, all of which are optionally substituted with:
second (C 1-6 )alkyl or second (C 3-7 )cycloalkyl, said second alkyl or second cycloalkyl being optionally substituted with a 6 or 10-membered aryl or Het; or
OR 101 ,COOR 101 or CONH 2 , wherein each R 101 is independently H or (C 1-6 )alkyl;
b) OR 104 wherein R 104 is H or (C 1-6 alkyl) optionally substituted with: COOH, COO(C 1-6 )alkyl or CONH 2 ;
d) SR 108 wherein R 108 is H or (C 1-6 )alkyl optionally substituted with COOH, COO(C 1-6 )alkyl or CONH 2 ;
e) NR 111 R 112 wherein R 111 and R 112 are both H; or R 111 is H and
R 112 is Het optionally substituted with (C 1-6 )alkyl, CONH 2 or COOR 115 wherein R 115 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
j) COOH or COO(C 1-6 )alkyl;
k) CONR 129 R 130 wherein R 129 and R 130 are each independently H or (C 1-6 )alkyl optionally substituted with COOH or COO(C 1-6 )alkyl; and
l) 6- or 10-membered aryl or Het, said aryl or Het being optionally substituted with from 1 to 4 substituents selected from:
i) (C 1-6 )alkyl or haloalkyl;
ii) OR 104 wherein R 104 is H, or (C 1-6 )alkyl) optionally substituted with COOH or COO(C 1-6 )alkyl; and
iii) COOR 128 , NR 111 R 112 or CON(R 129 R 130 ) 2 , wherein R 128 , R 111 , R 112 , R 129 and R 130 are independently H or (C 1-6 )alkyl.
43. A compound according to claim 1 , having the following formula:
wherein
D is CH or C(C 1-6 )alkyl;
B is CH, or C(C 1-6 )alkyl;
R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl, 6- or 10-membered aryl, Het, (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het;
or R 3 and R 4 are covalently bonded together to form second (C 3-7 )cycloalkyl, 5- or 6-membered heterocycle having from 1 to 4 heteroatom selected from O, N, and S;
wherein said alkyl, first and second cycloalkyl, aryl, Het, (C 1-6 )alkyl-aryl, (C 1-6 )alkyl-Het or heterocycle are optionally substituted with from 1 or 2 substituents selected from:
a) (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 2-4 )alkenyl; and
c) OR 31 or COOR 31 , wherein R 31 is H or (C 1-6 )alkyl; and
A′ is a 6- or 10-membered aryl, Het or (C 1-6 )alkyl-CONH-aryl, said aryl or Het being optionally substituted with:
halogen, or
1 to 2 substituents selected from:
a) (C 1-6 )alkyl, (C 1-6 ) haloalkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl, (C 2-8 )alkynyl, all of which are optionally substituted with:
second (C 1-6 )alkyl or second (C 3-7 )cycloalkyl, said second alkyl or second cycloalkyl being optionally substituted with a 6 or 10-membered aryl or Het;
OR 101 , COOR 101 or CONH 2 , wherein each R 101 is independently H or (C 1-6 )alkyl;
b) OR 104 wherein R 104 is H or (C 1-6 alkyl) optionally substituted with: COOH, COO(C 1-6 )alkyl or CONH 2 ;
d) SR 108 wherein R 108 is H or (C 1-6 )alkyl optionally substituted with COOH, COO(C 1-6 )alkyl or CONH 2 ;
e) NR 111 R 112 wherein R 111 and R 112 are both H; or R 111 is H and R 112 is Het optionally substituted with (C 1-6 )alkyl, CONH 2 or COOR 115 wherein R 115 is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, or (C 1-6 )alkyl-(C 3-7 )cycloalkyl;
j) COOH or COO(C 1-6 )alkyl;
k) CONR 129 R 130 wherein R 129 and R 130 are each independently H or (C 1-6 )alkyl optionally substituted with COOH or COO(C 1-6 )alkyl; and
l) 6- or 10-membered aryl or Het, said aryl or Het being optionally substituted with from 1 to 4 substituents selected from:
i) (C 1-6 )alkyl or haloalkyl;
ii) OR 104 wherein R 104 is H, or (C 1-6 )alkyl) optionally substituted with COOH or COO(C 1-6 )alkyl; and
iii) COOR 128 , NR 111 R 112 or CON(R 129 R 130 ) 2 , wherein R 128 , R 111 , R 112 , R 129 and R 130 are independently H or (C 1-6 )alkyl.
44. A compound of formula Ia:
wherein R 1 is selected from: 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S and phenyl, said heterocycle and phenyl being optionally substituted with from 1 to 4 (C 1-4 )alkyl substituents;
R 2 is selected from: (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-3 )alkyl, and norbornane;
X is CH;
R 6 is H or (C 1-6 alkyl);
Y is O or S;
B is CR 5 , wherein R 5 is H or (C 1-6 )alkyl;
Z is O, N, or NH;
W is CR 3 R 4 wherein R 3 and R 4 are each independently H, (C 1-6 alkyl), (C 3-7 cycloalkyl), (C 1-6 alkyl)phenyl, (C 1-6 alkyl)-(C 3-7 cycloalkyl), (C 3-7 cycloalkyl)-(C 1-6 alkyl), (C 3-7 cycloalkyl)-(C 2-4 alkenyl), (C 1-6 alkyl)-OH, phenyl; CH 2 biphenyl, 5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from O, N, and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, (C 1-6 alkyl)-5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from O, N, and S, or (C 1-6 alkyl)-9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, or R 3 and R 4 are covalently bonded together to form (C 3-7 cycloalkyl), 4-, 5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from O, N, and S; or when Z is N, either R 3 or R 4 is covalently bonded thereto to form a 5-membered heterocycle;
wherein said alkyl, cycloalkyl, heterocycle, heterobicycle, phenyl are optionally substituted with from 1 to 4 substituents selected from: OH, COOH, (C 1-6 alkyl), (C 2-4 alkenyl), CONH 2 , NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , NHCOCOOH, NHCOCON(C 1-6 alkyl) 2 , NHCOCONH(C 1-6 alkyl), SH, S(C 1-6 alkyl), NHC(═NH)NH 2 , and COO(C 1-6 alkyl);
R 7 is H or (C 1-6 alkyl);
A is selected from: (C 1-3 alkyl)CONHaryl, 6- or 10-membered aryl, biphenyl, 5- or 6-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S;
wherein said aryl, biphenyl, first heterocycle, and heterobicycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH, COO(C 1-6 )alkyl, (C 1-6 )alkyl, (C 1-6 )alkylCOOH, (C 1-6 alkyl)(C 2-4 alkynyl), (C 1-6 )alkyl-hydroxy, phenyl, benzyloxy, halogen, (C 2-4 )alkenyl, (C 2-4 )alkenyl-(C 1-6 )alkyl-COOH, 5- or 6-membered second heterocycle having 1 to 4 heteroatoms selected from O, N and S, NH-5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S,
wherein said second heterocycle and phenyl being optionally substituted with from 1 to 4 substituents selected from: (C 1-6 alkyl), CF 3 , OH, (C 1-6 alkyl)COOH, O(C 1-6 alkyl)COOH, (C 1-6 alkyl) COO(C 1-6 alkyl), CH 2 phenyl, COO(C 1-6 alkyl), (C 1-6 alkyl)O(C 1-6 alkyl), COOH, NCH(C 1-6 alkyl) 2 , NCO(C 1-6 alkyl), NH 2 , NH(C 1-6 alkyl), and N(C 1-6 alkyl) 2 ;
halogen, OPO 3 H, benzyl, sulfonamido, SH, SOCH 3 , SO 3 H, SO 2 CH 3 , S(C 1-6 alkyl)COOH, —CONH 2 , —COCH 3 , (C 1-3 )alkyl, (C 2-4 alkenyl)COOH
wherein said alkenyl is optionally substituted with from 1 to 2 (C 1-6 alkyl) substituents,
(C 2-4 alkenyl)COO(C 1-6 alkyl), tetrazolyl, COOH, triazolyl, OH, NO 2 , NH 2 , —O(CH 2 ) p COOH, hydantoin, benzoyleneurea, (C 1-4 )alkoxy, (C 1-4 )alkoxy(C 1-6 alkyl)COOH, cyano, azido, —O—(C 1-6 )alkyl COOH, —O—(C 1-6 )alkyl COO—(C 1-6 )alkyl, —NHCOCOOH, —NHCOCONHOH, —NHCOCONH 2 , —NHCOCONHCH 3 , —NHCO(C 1-6 )alkyl-COOH, —NHCOCONH(C 1-6 )alkyl-COOH, —NHCO(C 3-7 )cycloalkyl-COOH, —NHCONH(C 6-10 )aryl-COOH, —NHCONH(C 6-10 )aryl-COO(C 1-6 )alkyl, —NHCONH(C 1-6 )alkyl-COOH, —NHCONH(C 1-6 )alkyl-COO(C 1-6 )alkyl, —NHCONH(C 1-6 )alkyl-(C 2-6 )alkenyl-COOH, —NH(C 1-6 )alkyl-(C 6-10 )aryl-O(C 1-6 )alkyl COOH, —NH(C 1-6 )alkyl-(C 6-10 )aryl-COOH, —NHCH 2 COOH, —NHCONH 2 , —NHCO(C 1-6 )hydroxyalkyl COOH, —OCO(C 1-6 )hydroxyalkyl COOH, (C 3-6 )cycloalkyl COOH,
—NHCHO, —NHSO 2 CH 3 , —NHSO 2 CF 3 , coumarin, (C 1-6 )alkyl-amino, di-(C 1-6 )alkyl-amino, C(halogen) 3 , —NH(C 2-4 )acyl, —NH(C 6-10 )aroyl, —CONH(C 1-6 alkyl), —CO(C 1-6 )alkyl-COOH, —CONH(C 1-6 )alkyl-COOH, —CO—NH-alanyl, —CONH(C 2-4 )alkylN(C 1-6 alkyl) 2 , —CONH(C 2-4 )alkyl-Het-CONH(C 2-4 )alkyl-(COOH)-Het-CONH(C 1-2 alkyl) (OH)(C 1-2 alkyl) OH, —CONH(C 1-6 )alkyl-COOH, —CONH(C 6-10 aryl), —CONH-Het-CONH(C 6-10 ) aryl-COOH, —CONH(C 6-10 ) aryl-COO(C 1-6 )alkyl, —CONH(C 1-6 )alkyl-COO(C 1-6 )alkyl, —CONH(C 6-10 ) aryl-(C 1-6 )alkyl-COOH, —CONH(C 6-10 )aryl-(C 2-6 )alkenyl-COOH;
or salt thereof;
with the proviso that when R 1 is a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, R 2 is (C 3-7 )cycloalkyl, Y is O, Z is NH, one of R 3 and R 4 is optionally substituted (C 1-6 alkyl)phenyl, optionally substituted CH 2 biphenyl, optionally substituted (C 1-6 alkyl)-5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from O, N, and S, or optionally substituted (C 1-6 alkyl)-9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, and R 7 is H, then A is not optionally substituted 5- or 6-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S or optionally substituted 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S.
45. A compound according to claim 1 having the following formula:
wherein R 3 , R 4 and A are as defined below:
Cmpd. # A 1001 ; 1002 ; 1003 ; 1004 ; 1005 ; 1006 ; 1007 ; 1008 ; 1009 ; 1010 ; 1011 ; 1012 ; 1013 ; 1014 ; 1015 ; 1016 ; 1017 ; 1018 ; 1019 ; 1020 ; 1021 ; 1022 ; 1023 ; 1024 ; 1025 ; 1026 ; 1027 ; 1028 ; 1029 ; 1030 ; 1031 ; 1032 ; 1033 ; 1034 ; 1035 ; 1036 ; 1037 ; 1038 ; 1039 ; 1040 ; 1041 ; 1042 ; 1043 ; 1044 ; 1045 ; 1046 ; 1047 ; 1048 ; 1049 ; 1050 ; 1051 ; 1052 ; 1053 ; 1054 ; 1055 ; 1056 ; 1057 ; 1058 ; 1059 ; 1060 ; 1061 ; 1062 ; 1063 ; 1064 ; 1065 ; 1066 ; 1067 ; 1068 ; 1069 ; 1070 ; 1071 ; 1072 ; 1073 ; 1074 ; 1075 ; 1076 ; 1077 ; 1078 ; 1079 ; 1080 ; 1081 ; 1082 ; 1083 ; 1084 ; 1085 ; 1086 ; 1087 ; 1088 ; 1089 ; 1090 ; 1091 ; 1092 ; 1093 ; 1094 ; 1095 ; 1096 ; 1097 ; 1098 ; 1099 ; 1100 ; 1101 ; 1102 ; 1103 ; 1104 ; 1105 ; 1108 ; 1109 ; 1110 ; and 1111 .
46. A compound according to claim 1 having the following formula:
wherein R 1 , R 2 , R 3 , and R 4 are as defined below:
Cmpd. # R 1 R 2 2001 ; 2002 ; 2003 ; 2004 ; 2005 ; 2006 ; 2007 ; 2008 ; 2009 ; 2010 ; 2011 ; 2012 ; 2013 ; 2014 ; 2015 ; 2016 ; 2017 ; 2018 ; 2019 ; 2020 ; 2021 ; 2022 ; 2023 ; 2024 ; 2025 ; 2026 ; 2027 ; 2028 ; 2029 ; 2030 ; 2031 ; 2032 ; 2033 ; 2034 ; 2035 ; 2036 ; 2037 ; 2038 ; 2039 ; 2040 ; 2041 ; 2042 ; 2043 ; 2044 ; 2045 ; 2046 ; 2047 ; 2048 ; 2049 ; 2050 ; 2051 ; 2052 ; and 2053 .
47. A compound to according to claim 1 having the following formula:
wherein B and D are defined below:
Compound entry # B D 3002 CH CMe; and 3003 CMe CH.
48. A pharmaceutical composition for the treatment of HCV infection, comprising an effective amount of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
49. A composition according to claim 48 , further comprising an immunomodulatory agent.
50. A composition according to claim 49 , wherein said immunomodulatory agents is selected from: α-, β-, δ-γ-, and ω-interferon.
51. A composition according to claim 48 , further comprising another antiviral agent.
52. A composition according to claim 51 , wherein said antiviral agent is selected from: ribavirin and amantadine.
53. A composition according to claim 48 , further comprising another inhibitor of HCV polymerase.
54. A composition according to claim 48 , further comprising an inhibitor of HCV selected from: HCV helicase, HCV protease, HCV metalloprotease or HCV IRES.
55. A compound of the formula I, according to claim 1 , or a pharmaceutically acceptable salt thereof, as an inhibitor of HCV replication.
56. An intermediate compound of formula (i):
wherein R 1 , R 2 , R 3 , R 4 , B, D, X, Y 1 , and Z are as defined in claim 1 , or a derivative thereof.
57. An intermediate compound of formula I(ii):
wherein R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, Y 1 , Y 2 and Z are as defined in claim 1 , or a derivative thereof.
58. A process for producing compounds of formula I,
wherein R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, Y 1 , Y 2 and Z are as defined in claim 1 , comprising:
a) removing, in a mixture of an aqueous base or an aqueous acid in a co-solvent, the protecting group (PG) from:
wherein R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, Y 1 , Y 2 and Z are as defined in claim 1 , and wherein PG is a carboxylic acid protecting group, so as to produce compounds of formula I.
59. A process for producing compounds of formula I,
wherein R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, Y 1 , Y 2 and Z are as defined in claim 1 , comprising:
a) cleaving, under acidic conditions, intermediate compound I (ii)
so as to produce compounds of formula I, where R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, Y 1 and Y 2 are as defined in claim 1 .
60. A process for producing compounds of formula I,
wherein R 1 , R 2 , R 3 , R 4 , R 7 , A, B, D, X, and Z are as defined in claim 1 , comprising:
i) coupling intermediate compound of formula (i):
wherein R 1 , R 2 , R 3 , R 4 , B, D, X, and Z are as defined in claim 1 , or a derivative thereof, with HN(R 7 )—A wherein R 7 and A are as defined in claim 1 , to produce a compound of formula I.
61. A method of treating HCV infection in a mammal, comprising administering to the mammal an effective amount of a compound of formula I, according to claim 1 , or a pharmaceutically acceptable salt thereof.
62. A method of treating HCV infection in a mammal, comprising administering to the mammal an effective amount of a compound of formula I, according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with another anti-HCV agent.Cited by (0)
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